Sequential ALK inhibitor treatment benefits patient with leptomeningeal metastasis harboring non‐EML4‐ALK rearrangements detected from cerebrospinal fluid: A case report

Abstract

A 47‐year‐old female with ALK‐rearranged lung adenocarcinoma developed leptomeningeal metastasis (LM) after progression on first‐line crizotinib. Alectinib 300 mg was commenced and the patient achieved clinical and radiographic improvements. After nine months of alectinib 300 mg, she started to experience symptomatic LM. Two concurrent non‐EML4‐ALK rearrangements, LOC388942‐ALK and LINC00211‐ALK, were identified from the CSF but not from the plasma samples. With the primary lung lesions remaining stable, the alectinib dose was increased to 600 mg twice daily which alleviated the clinical symptoms of symptomatic LM. After 7.6 months of alectinib 600 mg, the patient again experienced CNS progression. With both CSF and plasma samples revealing no druggable mutations, the alectinib dose was re‐escalated to 900 mg twice daily, resulting in clinical benefits lasting for two months. Her therapy was then switched to lorlatinib which controlled the disease for 8.7 months until her demise. The LINC00211‐ALK fusion, which retains the ALK kinase domain, detected from the CSF was the mechanism of treatment efficacy in this patient. The central nervous system (CNS) has been increasingly recognized as a site of treatment failure in multiple cancers, including non‐small cell lung cancer (NSCLC). Our case demonstrated that alectinib dose‐escalation and lorlatinib overcame ALK inhibitor resistance in the CNS in an ALK‐positive LM patient. Furthermore, we provide the first clinical evidence of the efficacy of sequential ALK inhibitors in targeting LINC00211‐ALK in a patient with LM.

Detection of Nonreciprocal/Reciprocal ALK Translocation as Poor Predictive Marker in Patients With First-Line Crizotinib-Treated ALK-Rearranged NSCLC

“…3,[5][6][7][8][9][10][11] With the development of gene-sequencing technologies, more non-EML4-ALK fusions are being identified, with their responses to crizotinib reported in several case reports. [12][13][14][15] Crizotinib is the first tyrosine kinase inhibitor approved by the US Food and Drug Administration in 2011 for ALK-rearranged NSCLCs, and its efficacy has been comprehensively verified in a series of clinical trials. 16,17 Despite dramatic responses to crizotinib therapy, the response duration of patients treated with crizotinib varies and emerging data suggest that the EML4-ALK breakpoint variants or ALK fusion partners affect clinical outcomes.…”

Leptomeningeal Metastases: New Opportunities in the Modern Era

“…Investigation of a German early access program revealed a partial response rate of 77.8% among 9 patients with LM, but did not provide further details regarding duration of response [90]. While these expanded access datasets are limited due to their retrospective nature and lack of protocolized neuraxial assessments, they complement a number of case reports demonstrating improvement of both LM disease burden and neurologic symptoms following lorlatinib treatment [91][92][93].…”

Leveraging Molecular and Immune-Based Therapies in Leptomeningeal Metastases

“…CSF sampling of 10 total patients treated with lorlatinib 100 mg daily in phase I/II studies revealed a CSF-to-plasma ratio of 0.73 [92] and 0.77 [93], far higher than what had been previously demonstrated for crizotinib. Prospective studies of lorlatinib in patients with LM are lacking, however a phase II subgroup analysis and several case reports in patients with ALK+ LM have highlighted rapid symptom improvement and long-lasting intracranial responses, ranging 8-22 months [88,[94][95][96]. The largest cohort analysis of leptomeningeal activity of lorlatinib derives from an international early/expanded access program of 95 previously TKI-treated patients, in which 11 evaluable patients with LM (9 ALK+ and 2 ROS1+) achieved an intracranial ORR of 45% (95% CI 17-77) and DCR of 91% (95% CI 59-100) [97].…”